irinotecan/cisplatin with or without simvastatin in chemo-naive patients with extensive disease-small cell lung cancer

Conditions: Small Cell Lung Carcinoma

Summary: the purpose of this study is to compare the efficacy of simvastatin and irinotecan/cisplatin chemotherapy with irinotecan/cisplatin chemotherapy alone in extensive disease-small cell lung cancer.

statins (3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitors) have been used to treat hypercholesterolemia. besides the lipid lowering effects, they also act as anti-inflammatory and anti-cancer agents. recently the investigators demonstrated a synergistic cytotoxicity between simvastatin and irinotecan in human lung cancer cells. simvastatin enhances irinotecan-induced apoptosis by inhibition of proteasome activity. all of these additional actions may counteract harmful effects of smoking-induced chronic inflammation. these properties together with a high safety profile have made statins more attractive drug for small cell lung cancer (sclc), the highly smoking-related cancer. given the promising preclinical anti-tumor and anti-inflammatory effects of simvastatin in sclc, recently the investigators conducted a phase ii study of simvastatin and irinotecan/cisplatin (ip) chemotherapy in chemo-naïve- patients with extensive disease-small cell lung cancer (ed-sclc). the 1-year survival rate was 39.3%. the median overall survival (os) and progression free survival (pfs) was 11.0 months and 6.1 months, respectively. overall relative risk (rr) was 75%. the most common toxicity was neutropenia (67%). the efficacy was significantly associated with smoking-status. compared with never-smokers, ever-smokers had higher rr (40% v 78%, p=0.01) and longer pfs (2.5 months v 6.4 months, p=0.018) and showed a trend toward improved os (9.0 months v 11.2 months, p=0.095). the effect of smoking on survival was apparent when subdividing ever smokers according to pack-years (py). ever-smokers who smoked \> 65 py showed significantly longer os compared to ever-smokers who smoked \ 65 was predictive for longer survival (hazard ratio) hr=0.377 \[95% ci (confidence interval), 0.157-0.905\]). these findings suggest that the addition of simvastatin to irinotecan and cisplatin improved efficacy in ever-smokers with ed-sclc. the survival benefit of this combination seems apparent in heavy-smokers.

Eligibility criteria:
inclusion criteria: * histologically confirmed sclc * extensive - stage disease, defined as disease extending beyond one hemithorax or involving contralateral mediastinal, hilar or supraclavicular lymph nodes, and/ or pleural effusion * ever smoker( have smoked\> 100 cigarettes in entire lifetime * no prior chemotherapy, immunotherapy, or radiotherapy * measurable disease according to recist 1.1 * patient compliance that allow adequate follow - up * adequate hematologic , hepatic and renal function. * written informed consent that is consistent with international conference on harmonization (ich) - good clinical practice (gcp) guidelines * males of females at least 18 years of age * if female : childbearing potential either terminated by surgery, radiation, or menopause or attenuated by use of an approved contraceptive method(intrauterine device, birth control pills, or barrier device)during for 3 months after trial. if male, use of an approved contraceptive method during the study and 3 months afterwards. females with childbearing potential must have a urine negative hcg test within 7 days prior to the study enrollment. * no concomitant prescriptions including cyclosporin a, valproic acid, phenobarbital, phenytoin, ketoconazole. * patients with brain metastasis are allowed unless there were clinically significant neurological symptoms or signs. exclusion criteria: * inability to comply with protocol or study procedures. * a serious concomitant systemic disorder that, in the opinion of the investigator, would compromise the patient's ability to complete the study. * a serious cardiac condition, such as myocardial infarction with 6 months, angina, or heart disease, as defined by the new york heart association class iii or iv. * second primary malignancy that is clinically detectable at the time of consideration for study enrollment. * concurrent administration of any other antitumor therapy. * pregnant or breast-feeding. * taking simvastatin or any contraindications for therapy with simvastatin

Keywords: simvastatin sclc extensive disease